“Peripheral” androgen deprivation for men with a rising PSA after surgery and/or radiation therapy


What is the best type of treatment to offer a man after primary and (perhaps) appropriate secondary forms of treatment leave him with a rising PSA?

Historically, the standard “next step” for a man with such a rising PSA (biochemical progression) after first-line radiation therapy or first-line surgery and second-line radiation therapy has been androgen deprivation therapy (ADT) with either a short course of an antiandrogen (normally bicalutamide or flutamide) and longer-term use of an LHRH agonist (e.g., leuprolide acetate) or combined ADT with a long course of an antiandrogen and an LHRH agonist. A subset of men has been managed with various types of intermittent ADT, sometimes including a 5α-reductase inhibitor (5-ARI) like finasteride or dutasteride as well.

A new article by Monk et al., published on line in Cancer in December, now offers us a different opportunity based on 10 years of follow-up of men managed with “peripheral” androgen deprivation (PAD) using a combination of an antiandrogen and a 5-ARI. This opportunity needs to be tested in a major, randomized, multicenter, Phase III clinical trial. (Additional information about the results of this trial are available in a report published on the Medscape web site.)

Monk et al. report enrollment of 101 patients with progressive prostate cancer into this multicenter study. All the patients had received “definitive local therapy” (although the details of this therapy are not available in the abstract of the paper). They also had a rising PSA (> 1 ng/ml) but there was no other evidence of recurrent disease. They were all treated with PAD using an antiandrogen (flutamide, 250 mg t.i.d.) and a 5-ARI (finasteride, 5 mg once daily) and followed to assess their PSA response and their quality of life.

Here are the results reported by Monk and his colleagues:

  • 99/101 patients enrolled (98 percent) were eligible for assessment.
  • The 5-year overall survival rate was 87 percent.
  • The 5-year metastasis-free survival rate was 97 percent.
  • Median follow-up is now 10 years.
  • 22/99 patients (22 percent) remain on therapy.
  • 43/99 patients (43 percent) have died (including 13 who died of progressive prostate cancer), which means that median overall survival has still not been reached.
  • A decrease of ≥ 80 percent in patient’s PSA levels was observed in 96/99 patients (97 percent).
  • PSA became undetectable (i.e., <0.2 ng/ml) in 72/99 patients (73 percent).
  • The median time to a nadir PSA value was 3.2 months.
  • The average (median) time to biochemical progression was 85 months (> 7 years).
  • 18/99 patients (18 percent) stopped therapy because of side effects of treatment.
    • 15 patients had diarrhea.
    • 4 patients had gynecomastia.
    • 3 patients had elevated levels of liver enzymes.
  • There was a small but significant decrease in quality of life scores at 6 months post-enrollment in this trial.

It is worth noting that one of the rationales for this study was that PAD does not suppress serum testosterone levels in the same way that medical castration (with an LHRH agonist) or surgical castration (an orchiectomy) do.

Clearly PAD based on an antiandrogen and a 5-ARI “works.” And it appears to work with less than optimal agents. In general, it would be reasonable to think that if the combination of finasteride and flutamide can have this effect, then the combination of dutasteride (Avodart) and bicalutamide (Casodex) might work at least as well and perhaps with fewer side effects. (Bicalutamide does not have the same tendency to induce diarrhea that is common in patients taking flutamide.)

The “New” Prostate Cancer InfoLink is not aware of any other study that is addressing this precise use of PAD. There has been a study of dutasteride used alone in similar patients. Some data are provided on the ClinicalTrials.gov web site, but as far as we are aware there has been no formal publication of results of this trial, and it is certainly the case that the patients in this trial were followed for significantly less than an average of 10 years.

7 Responses

  1. In light of this study is there an implication that those on LHRH agonist treatment at present would be better (or at least no worse) off switching to this PAD treatment?

  2. Dear Dr. Kline:

    I don’t believe we have a clear answer to that question at the present time. You should certainly feel able to bring that question up with your physicians, but don’t be too surprised if they respond by saying that the above-mentioned trial doesn’t justify such a decision.

    Of course there is always the “Well … what if I just wanted to try it anyway?” approach.

  3. This approach, called Sequential Androgen Blockade by Dr. Strum, has been around for many years. Unfortunately, it was necessary to take the time and efforts of these authors and their patients to “prove it.” Today, I think the use of bicalutamide (Casodex) might have fewer side effects.

    Herb S.

  4. I did this for 5 years until my PSA hit 1.5 ng/ml. I took 50 mg of Casodex three times a week and Avodart every day.

    Stu

  5. As noted by Herb, above, this protocol, known as Sequential Androgen Blockade (SAB) was tested and in practice 10 years ago. As Dr. Strum in his collaborated book with Donna Pogliano (A Primer on Prostate Cancer — The Empowered Patient’s Guide noted back then, this protocol was tested by Wheeler et al. for patients prior to any other treatment considered to have apparent organ-confined disease and prescribed for testosterone preservation (enabling sexual function as well as somewhat better quality of life) or for those who were unable to tolerate the effects of an LHRH agonist.

    Back then with a baseline PSA of 10.95 ng/ml a PSA nadir of 0.59 ng/ml was reached by 60.06 days, thus a net change in PSA of 10.36 ng/ml. In the Wheeler study, after a reduction in gland volume, reining in prostate cancer development, and PSA levels reduced below 2.0 ng/ml, this protocol was stopped and patients eventually moved to one of the therapy options to eradicate prostate cancer. See the “Primer” pages 149-150, B22, and B24-25.

  6. The protocol tested by Wheeler et al. and discussed by Strum and Pogliano was not, in fact, the same protocol as that discussed above at all.

    The Wheeler protocol (dependiong on how you want to look at it) was a strategy to lower PSA (and reduce prostate size), either as a first-line therapy or potentially prior to first-line therapy, and (as far as I am aware) no one ever tested this for a period of even 5 years, let alone a decade, to see if that strategy was effective.

    By comparison, the study described above discusses a second-line (or possibly a third-line) treatment strategy for men with progressive prostate cancer, and shows that PSA progression can be deferred for 10 years or more in a significant percentage of men with progressive disease, which is a rather different case scenario.

    I am not saying that no one has ever tried this type of periperal androgen ablation before. They have. However, what I am not aware of are any other data that show that this actually works in a large series of men followed for > 5 years. I would also point out that since this study is a simple cohort study, we do not know if this strategy is associated with a prostate cancer-specific or an overall survival benefit (which is one reason why we need a large, randomized, Phase III trial.

  7. My point, Sitemaster, is that the prescribing of an antiandrogen in company with a 5-ARI is not a new practice but one that has been prescribed for several years; not just as a pre-treatment brief period, but for men with recurring disease who, it seems more likely, wanted to hang on to their sexual/erectile capability as long as possible. And yes, I would like to see some statistics as to the length of time this procedure remained effective before either an LHRH agonist needed to be added, or the patient had to move on to other medications.

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